This project includes vaccine production and preclinical laboratory studies needed to initiate two clinical trials of an investigational smallpox vaccine that consists of a highly attenuated vaccinia virus that cannot replicate in human cells. It is expected to have a better safety profile than the traditional smallpox vaccines. One clinical study will be for vaccinia-naive individuals and the other for individuals previously immunized with vaccinia. The clinical trial designs are phase I/II, randomized, placebo-controlled, double-blinded, schedule-finding studies of MVA. The hypothesis is that MVA will be safe in humans when administered by intramuscular (IM) injection and will result in an immune response comparable to that observed after Dryvax primary vaccination. Subjects will be randomized to injections of MVA or placebo. This will be followed by Dryvax challenge 12 weeks later. Safety and immunogenicity lab tests will be done throughout the studies.